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More than meets the eye: Expanding and reviewing the clinical and mutational spectrum of brittle cornea syndrome
Author(s) -
Dhooge Tibbe,
Van Damme Tim,
Syx Delfien,
Mosquera Laura M.,
Nampoothiri Sheela,
Radhakrishnan Anil,
SimsekKiper Pelin O.,
Utine Gülen E.,
Bonduelle Maryse,
Migeotte Isabelle,
Essawi Osama,
Ceylaner Serdar,
Al Kindy Adila,
Tinkle Brad,
Symoens Sofie,
Malfait Fransiska
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24199
Subject(s) - connective tissue disorder , osteogenesis imperfecta , connective tissue , ehlers–danlos syndrome , cornea , biology , marfan syndrome , genetics , pathology , dermatology , medicine , anatomy , neuroscience
Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non‐ocular symptoms include not only hearing loss but also signs of connective tissue fragility, placing it in the Ehlers‐Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5 , which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5 . We also performed a genotype‐ and phenotype‐oriented literature overview of all ( n = 85) reported patients with ZNF469 ( n = 53) and PRDM5 ( n = 32) variants. Musculoskeletal findings may be the main reason for referral and often raise suspicion of another heritable connective tissue disorder, such as kyphoscoliotic EDS, osteogenesis imperfecta, or Marfan syndrome, especially when a corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition.